This Program Project Grant (PPG) application seeks to discover and characterize synthetic, small molecule compounds that may be effective in the treatment of human cancer. Four interrelated projects are proposed. The first project will employ the tools of biochemistry and molecular biology to discover the molecular targets of three natural products known to have potent cytotoxic activity. The second project will employ a peptidomimetic approach to discover synthetic organic compounds capable of rendering tumor cells susceptible to programmed cell death. The third project will employ both a high throughput screening (HTS) approach and a structure-activity-relationship (SAR) by nuclear magnetic resonance (NMR) approach to discover synthetic organic compounds capable of inhibiting an entirely novel growth regulatory pathway. The final project will employ both an HTS approach and an SAR-by-NMR approach to discover synthetic organic compounds capable of inhibiting the hypoxia response pathway of mammalian cells. All four of these projects will entail the combined use of chemical, biophysical and biochemical/molecular biological research. The goals of this PPG application could not be met without the unified contribution of the chemists, biophysicists and biologists that form the leadership structure of the PPG team. A unique and critical aspect of the research program will entail the development and use of a core facility for high throughput drug screening (HTS). This facility will have access to a library of 350,000 diverse, heterocyclic drug-like chemicals. Two of the four projects will make specific use of the HTS core facility for the critical objective of discovering small, synthetic compounds capable of modulating specific intracellular pathways that are highly relevant to human cancer. Beyond serving as the direct financial support for the proposed research objectives unique to this application, funding of this PPG will substantially enhance research at the interface of chemical and biomedical science at the host institution.